PROJECT SUMMARY Autophagy is a cell homeostasis process that involves self-digestion of cellular components. The substrates of autophagy are enclosed in double-membraned autophagosomes that fuse with lysosomes for degradation. Autophagy is essential for maintaining cell and tissue integrity, and is implicated in a number of diseases and conditions. While autophagy has been widely studied in degrading cytoplasmic components, its role in degrading nuclear materials is poorly understood. I recently discovered that autophagy degrades nuclear lamina in response to tumorigenic stress, such as activated oncogenes and DNA damage. This autophagic degradation is through nuclear lamina interaction with autophagy proteins in the nucleus, and a subsequent nucleus-to-cytoplasm transport, leading to degradation by the cytoplasmic autophagosomes and lysosomes. This discovery was one of the first illustrations of mammalian autophagy degrading nuclear components, a process termed as nuclear autophagy. The identification of the first nuclear substrate of autophagy prompted me to further investigate nuclear perspectives of mammalian autophagy. Nuclear autophagy is an emerging new field with tremendous potential to explore new research avenues. A central goal of my laboratory is to study the biology of nuclear autophagy and its implication in diseases. In this proposal, I aim to answer a major unaddressed area regarding the nuclear substrates that can be degraded by autophagy. The application has two directions. First, I propose to investigate a chromatin remodeling complex that is targeted by nuclear autophagy. Second, I propose to unbiasedly identify novel substrates of nuclear autophagy, employing advanced quantitative proteomics. My broad hypothesis is that the degradation of nuclear and chromatin constituents by autophagy mediates homeostasis of the nucleus, which is a central mechanism of cell stress responses. This study will pioneer a new research direction in the autophagy field, and may offer insights into several intersecting areas of biomedicine.